One approach to addressing the immense unmet need for treatments of severe opioid use disorder (sOUD) is to understand more about associated changes in the brain’s reward circuitry. It has been shown that during reward anticipation in the Monetary Incentive Delay (MID) task, people with severe substance use disorder (SUD) show blunted responses in reward neural circuitry compared with healthy controls (HC). Conversely, drug-related cues result in heightened responses in the same neural reward circuitry in those with SUD compared with HC. However, it is unclear how such dysfunctional reward processing is related to neural correlates of other processes commonly dysregulated in addiction, such as attention and cognition. The aim of this work was to evaluate whether people with sOUD show different relationships between reward networks to networks that regulate cognition, attention, sensory processes, and more. Then, we evaluated whether there is a spatial relationship between differences in brain function and atlases of μ-opioid receptor (MOR) and dopamine D2 receptor (DRD2) availability. We collected fMRI data while people with sOUD receiving methadone (MD; n = 25) and HC (n = 22) completed the MID and cue reactivity tasks. We evaluated differences in functional connectivity (FC) and measures of brain state dynamics. Partial least squared (PLS) analysis computed the spatial relationship between FC metrics to MOR and D2DR availability. We found that MD participants generally exhibited weaker miFC compared to HC in both tasks except when comparing the difference in miFC during anticipation of monetary reward or drug related stimuli vs neutral stimuli. Contrasts between rewarding or drug-related to neutral stimuli showed MD participants had stronger miFC between reward/anti-reward networks to regions in the control network and default mode Network (DMN) in both tasks. Analysis of brain state dynamics showed the DMN was more prevalent in MD participants during the MID task. PLS analysis showed spatial autocorrelation between MOR and D2DR availability and connectivity metrics during the MID task. These findings reveal distinct patterns of neural network interactions in individuals with sOUD, characterized by generally reduced FC but enhanced connections between reward-related networks and cognitive control regions in response to either monetary or drug-related cues vs neutral cues. We observed spatial correspondence between receptor availability and altered connectivity and dynamics in MD vs HC. These results provide new insights into the neural basis of reward processing dysfunction in sOUD and may inform the development of targeted neuromodulation therapeutic approaches. Clinical trial registration: This study is not a clinical trial and therefore was not registered as a clinical trial. The study design and planned analytical approach for the primary analyses was pre-registered [1]. This paper consists of secondary analyses which were not primary considerations when designing the research study that collected the data.

Abstract One approach to addressing the immense unmet need for treatments of severe Opioid Use Disorder (sOUD) is to understand more about associated changes in the brain’s reward circuitry. It has been shown that during reward anticipation in the Monetary Incentive Delay (MID) task, people with severe substance use disorder (SUD) show blunted responses in reward neural circuitry compared with healthy controls (HC). Conversely, drug-related cues result in heightened responses in the same neural reward circuitry in those with SUD compared with HC. However, it is unclear how such dysfunctional reward processing is related to neural correlates of other processes commonly dysregulated in addiction, such as attention and cognition. The aim of this work was to evaluate whether people with sOUD show different spatiotemporal relationships between reward networks to cognitive and attentional networks. We collected fMRI data while people with sOUD receiving methadone (MD; n = 22) and HC (n = 22) completed the MID and Cue Reactivity tasks. We evaluated differences in functional connectivity (FC) and measures of brain state dynamics. We explored the relationship between FC to µ-Opioid receptor (MOR) and Dopamine D2 Receptor (DRD2) availability due to their involvement in reward processing. During both the MID and Cue Reactivity tasks, MD participants showed significantly higher mutual information FC between regions in the reward network to those in attention and cognitive networks. We found significant, positive relationships between the higher FC in MD vs HC participants and the sum of MOR and D2 receptor availability during the Cue Reactivity task. In summary, the higher integration among reward, attentional, and cognitive networks in MD participants during both non-drug and drug-related tasks suggests that the relationship between these networks is dysregulated in addiction. These mechanistic insights provide alternative targets for treatment to improve sOUD outcomes.

Since the writing of Bacq's review, there have been major advances in both technology and knowledge of synaptic function. The basic observation of the pioneering work he describes is still true and chemical neurotransmission is an agreed fact but the complexity of the systems he describes has grown from a study of a handful of transmitters and receptors to more than 100 transmitters acting at several hundred different receptors. Cloning and expression of transmitter receptors and other synaptic proteins has allowed a much more detailed understanding of how transmitters work and facilitated the design and synthesis of antagonist molecules, some of which have become useful drugs. Techniques such as cryo-EM promise even more knowledge and understanding in the future.

BACKGROUND:Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. METHODS:This study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.

This review paper is based on a talk given at the British Pharmaceutical Society Winter Meeting in 2018 derived from the Home Office Report on the workings of the UK Psychoactive Substances Act (PSA) published in November 2018. The review deals with the context in which the PSA 2016 arose and how this piece of legislation differs from other UK drug regulations. It attempts to put the PSA in context with other control schemes being instituted around the world and to assess the success of the Act in its first 2 years of implementation. For more details the reader is referred to Review of the Psychoactive Substances Act 2016, Home Office, November 2018.

Animal pharmacology experiments to establish putative efficacy and to predict dose in subsequent human subject investigations have been, and continue to be, an important part of the drug discovery process. The predictive value of such animal work is sometimes minimal and this chapter reviews the reasons for this and suggests ways in which the most robust data can be obtained. The use of chiral molecules to obtain data that is reliably associated with the pharmacological target and the use of surrogate endpoints are considered. The problem of species differences in pharmacology is dealt with in the context of neuropharmacological studies of the role of substance P. The importance of imaging studies and ways in which reproducibility can be improved are also briefly considered.

The world of drug discovery has changed substantially during the past 20 years, and it is no longer the sole province of very large multinational companies. The present status might be best envisaged as a triangular relationship between small and large companies and academic research. In this environment, it is sometimes hard to see where early career researchers might forge a career.1Hill RG How the pharmaceutical industry is changing.Physiol News. 2013; 92: 27-29Google Scholar, 2Hill RG Hayes AG Hunter AJ Richards DB Current developments in drug discovery.in: UKSPA. Innovation into success. Ten Alps Publishing, London2013: 37-39Google ScholarThe most important thing a medical scientist brings to drug discovery research is clinical context and the ability to see where an early research project might (or might not) end up, in terms of patient care and risks or benefits. Although physician scientists, especially those with both medical and PhD training, are seen as desirable recruits by companies engaged in drug discovery and development, knowing when to join industry is key. Early stage researchers are unlikely to have the entire skill set needed to run a project. They will need to think about the best way to get on the job training to fill out their competence. A position with a large pharmaceutical or biotechnology company will carry a career development component with it, but smaller companies expect recruits to hit the ground running and rarely have the time or the money to worry about career development. Even if your long-term ambition is to work in a small company, it might make sense to work for a large company for, say, 5 years first to gain relevant experience and training.Most positions in industry are advertised in major scientific and medical journals. It is worth also checking company websites because this might be the first place (sometimes the only place for biotechnology startups) that a new position is announced. Occasionally head hunters are engaged to fill even more junior posts if there is a specific skill or experience requirement for the position in question. It is also quite common for senior scientists in industry to phone around their academic contacts for suggestions about suitable recruits, so developing your network is important. You might feel that this is hard, but every mentor you have had from your undergraduate years onwards is potentially useful to you. Taking every opportunity to be part of mentoring schemes and attend events where speakers from industry are present is very helpful in this regard.There are lots of benefits associated with a position in industry. It can provide interesting projects that are well funded (without the hassle of applying for grants!) and excellent facilities in terms of laboratories and equipment. Personal remuneration tends to be more generous than in academic life. A long-term career in industry can also provide great variety. Although you might be recruited for a specific project related to something you have worked on in your academic career, if that does not lead to a successful drug candidate and the project is terminated, you will be expected to turn your attention to something that might be very different. A flexible outlook is therefore highly recommended.If you are considering a transition into industry, it goes without saying that background research on both the requirements for the position you are taking up, and on what will be needed should you decide that industry is not for you and wish to return to an academic role or clinical practice is important. The more experienced you are in an environment the easier it will be to return to it. A move into industry too early in your career, before you have the opportunity to develop a substantial academic track record and publication list, might make returning to an academic position more difficult. Distinctions are now becoming blurred and a number of distinguished clinical scientists have 50:50 positions between major academic centres and a large company, which allows more flexibility for moving between both worlds.The life sciences sector is undergoing a period of rapid transformation. However, its success will continue to rely on the talent and skills of the upcoming generation of scientists.Prof Raymond Hill is a Visiting Professor of Pharmacology, Imperial College London, UK, and Fellow of the Academy of Medical Sciences. He has had extensive experience of working in the pharmaceutical industry and academia during the past 40 years. The world of drug discovery has changed substantially during the past 20 years, and it is no longer the sole province of very large multinational companies. The present status might be best envisaged as a triangular relationship between small and large companies and academic research. In this environment, it is sometimes hard to see where early career researchers might forge a career.1Hill RG How the pharmaceutical industry is changing.Physiol News. 2013; 92: 27-29Google Scholar, 2Hill RG Hayes AG Hunter AJ Richards DB Current developments in drug discovery.in: UKSPA. Innovation into success. Ten Alps Publishing, London2013: 37-39Google Scholar The most important thing a medical scientist brings to drug discovery research is clinical context and the ability to see where an early research project might (or might not) end up, in terms of patient care and risks or benefits. Although physician scientists, especially those with both medical and PhD training, are seen as desirable recruits by companies engaged in drug discovery and development, knowing when to join industry is key. Early stage researchers are unlikely to have the entire skill set needed to run a project. They will need to think about the best way to get on the job training to fill out their competence. A position with a large pharmaceutical or biotechnology company will carry a career development component with it, but smaller companies expect recruits to hit the ground running and rarely have the time or the money to worry about career development. Even if your long-term ambition is to work in a small company, it might make sense to work for a large company for, say, 5 years first to gain relevant experience and training. Most positions in industry are advertised in major scientific and medical journals. It is worth also checking company websites because this might be the first place (sometimes the only place for biotechnology startups) that a new position is announced. Occasionally head hunters are engaged to fill even more junior posts if there is a specific skill or experience requirement for the position in question. It is also quite common for senior scientists in industry to phone around their academic contacts for suggestions about suitable recruits, so developing your network is important. You might feel that this is hard, but every mentor you have had from your undergraduate years onwards is potentially useful to you. Taking every opportunity to be part of mentoring schemes and attend events where speakers from industry are present is very helpful in this regard. There are lots of benefits associated with a position in industry. It can provide interesting projects that are well funded (without the hassle of applying for grants!) and excellent facilities in terms of laboratories and equipment. Personal remuneration tends to be more generous than in academic life. A long-term career in industry can also provide great variety. Although you might be recruited for a specific project related to something you have worked on in your academic career, if that does not lead to a successful drug candidate and the project is terminated, you will be expected to turn your attention to something that might be very different. A flexible outlook is therefore highly recommended. If you are considering a transition into industry, it goes without saying that background research on both the requirements for the position you are taking up, and on what will be needed should you decide that industry is not for you and wish to return to an academic role or clinical practice is important. The more experienced you are in an environment the easier it will be to return to it. A move into industry too early in your career, before you have the opportunity to develop a substantial academic track record and publication list, might make returning to an academic position more difficult. Distinctions are now becoming blurred and a number of distinguished clinical scientists have 50:50 positions between major academic centres and a large company, which allows more flexibility for moving between both worlds. The life sciences sector is undergoing a period of rapid transformation. However, its success will continue to rely on the talent and skills of the upcoming generation of scientists. Prof Raymond Hill is a Visiting Professor of Pharmacology, Imperial College London, UK, and Fellow of the Academy of Medical Sciences. He has had extensive experience of working in the pharmaceutical industry and academia during the past 40 years.

Neuropeptides and kinins are important messengers in the nervous system and--on the basis of their anatomical localisation and the effects produced when the substances themselves are administered, to animals or to human subjects-a significant number of them have been suggested to have a role in pain and inflammation. Experiments in gene deletion (knock-out or null mutant) mice and parallel experiments with pharmacological receptor antagonists in a variety of species have strengthened the evidence that a number of peptides, notably substance P and calcitonin gene-related peptide (CGRP), and the kinins have a pathophysiological role in nociception. Clinical studies with non-peptide pharmacological antagonists are now in progress to determine if blocking the action of these peptides might have utility in the treatment of pain.

Este capitulo resume la situacion de la investigacion de nuevos farmacos en desarrollo para tratar el dolor, y describe los obstaculos que debe superar un nuevo farmaco antes de poder ser introducido como terapia. Incluye no solo la descripcion de los farmacos que se han descubierto intencionadamente como analgesicos sino tambien de los farmacos que se habian desarrollado inicialmente para otras indicaciones terapeuticas y que, posteriormente, han demostrado utilidad en el tratamiento del dolor. En esta revision se diferenciara aquellas nuevas moleculas que se han desarrollado a partir de la optimizacion de productos ya utilizados clinicamente y de las moleculas completamente nuevas en terminos de su mecanismo de accion. El capitulo se centra en los compuestos que se encuentran actualmente en desarrollo clinico o que estan muy cerca de esta situacion, ya que los farmacos en las fases mas iniciales del ciclo de desarrollo tienen una probabilidad muy baja de llegar a ser comercializados.

The process involved in the identification and development of novel breakthrough medicines at big pharma has recently undergone significant changes, in part because of the extraordinary complexity that is associated with tackling diseases of high unmet need, and also because of the increasingly demanding requirements that have been placed on the pharmaceutical industry by investors and regulatory authorities. In addition, big pharma no longer have a monopoly on the tools and enabling technologies that are required to identify and discover new drugs, as many biotech companies now also have these capabilities. As a result, researchers at biotech companies are able to identify credible drug leads, as well as compounds that have the potential to become marketed medicinal products. This diversification of companies that are involved in drug discovery and development has in turn led to increased partnering interactions between the biotech sector and big pharma. This article examines how Merck and Co Inc, which has historically relied on a combination of internal scientific research and licensed products, has poised itself to become further engaged in partnering with biotech companies, as well as academic institutions, to increase the probability of success associated with identifying novel medicines to treat unmet medical needs--particularly in areas such as central nervous system disorders, obesity/metabolic diseases, atheroma and cancer, and also to cultivate its cardiovascular, respiratory, arthritis, bone, ophthalmology and infectious disease franchises.

Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.

Over the last two decades much research has focused on the role of substance P in pain and on the development of substance P antagonists as novel analgesics. Despite the identification of high affinity and selective substance P (NK1) receptor antagonists and a plethora of preclinical data supporting an analgesic profile of these agents, the outcome from clinical trials has been extremely disappointing with no clear analgesic efficacy being observed in a variety of pain states. This has led the pain community to seriously question the predictability and utility of preclinical pain assays, especially for novel targets. This chapter will review the animal studies and clinical trials with NK1 receptor antagonists and suggests possible reason s for the apparent mismatch between preclinical and clinical studies in pain.

The opioid receptor-like 1 receptor is a novel member of the opioid receptor family and its endogenous peptide ligand has been termed nociceptin and orphanin FQ. Activation of the opioid receptor-like 1 receptor by nociceptin/orphanin FQ in vivo produces hyperalgesia when this peptide is given supraspinally but analgesia at the spinal level. Nociceptin/orphanin FQ also reverses stress-induced analgesia, suggesting that the peptide has anti-opioid properties. Nociceptin/orphanin FQ knockout mice show alterations in pain sensitivity and stress responses and display increased morphine dependence, suggesting an interaction of the nociceptin/orphanin FQ system with classical opioid receptor function. To determine if the behavioural phenotype of nociceptin/orphanin FQ knockout mice reflects changes in either opioid receptor-like 1 or classical opioid receptor expression, we have carried out quantitative autoradiography of the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains of these animals. Receptor density was measured on coronal sections from wild-type, heterozygous and homozygous mice using [(3)H]nociceptin, [(3)H][D-Ala(2)-N-methyl-Phe(4)-Gly(5) ol] enkephalin, [(3)H]deltorphin-I, or [(3)H](-)-N-methyl-N-[7-(1-pyrrodinyl)-1-oxospiro[4,5]dec-8-yl]-4-benzofuranacetamide to label opioid receptor-like 1, mu-, delta- and kappa-receptors, respectively. A region-specific up-regulation of the opioid receptor-like 1 receptor (up to 135%) was seen in brains from homozygous mice. Mu-Receptors also showed significant differences between genotypes whilst changes in delta- and kappa- receptors were minor. In conclusion the region-specific up-regulation of the opioid receptor-like 1 receptor indicates a tonic role for nociceptin/orphanin FQ in some brain structures and may suggest the peptide regulates the receptor expression in these regions. The changes in the opioid receptor-like 1 receptor may relate to the anxiogenic phenotype of these animals but the observed change in mu-receptors does not correlate with altered morphine responses.

The role of endogenous opioid peptides and receptors has recently been investigated using knockout mice. Although the affinities of opioid peptides for opioid receptors has been known for many years there is still some uncertainty over which receptor is the endogenous target for each peptide. To address this issue we have studied using quantitative autoradiography the levels of all four opioid receptor subtypes (μ, δ, κ and opioid receptor-like 1 [ORL1]) in brains sectioned from enkephalin and dynorphin knockouts, as well as from double knockouts. Because receptor up-regulation has been observed when its cognate ligand-peptide is genetically ablated, regional changes in receptor binding in knockout mice may reflect areas where the peptide ligand is tonically active at its receptor or played a role in receptor regulation. In addition, the study aimed to correlate previously observed behaviour in these animals with receptor modulation. Marked region-specific up-regulation of the μ, δ, and κ opioid receptors but not ORL1 receptors was observed in proenkephalin and prodynorphin knockouts. In proenkephalin knockouts this was most pronounced for the μ- and δ-receptor and in prodynorphin knockouts for the κ-receptor. Combinatorial double knockouts did not show any changes in addition to those observed in single knockouts. The largest changes were observed in limbic regions and our results suggest that proenkephalin peptides are tonically active at μ and δ-receptors predominantly in these areas. Prodynorphin peptides appear to regulate mostly the κ-receptor but they are also modulators of μ- and δ-receptors.

There are two bradykinin receptor subtypes, designated B1 and B2. Whilst both have been implicated in nociception, it is believed that there is a low level of constitutive expression of B1 receptors and that their expression is induced by inflammation or tissue damage. The present study investigated the role of B1 receptors in spinal nociceptive processing using an in vivo electrophysiological assay in decerebrate, spinalized rabbits, a species that shares close B1 receptor homology with the human receptor. Inflammation was induced in the paw by an injection of complete Freund's adjuvant at least 1 h before recording single motor unit activity of the semitendinous/biceps femoris muscle in response to a noxious pinch of the foot. Control animals received an intraplantar injection of saline. The peptide B1 receptor antagonist B9858 was administered i.v. and caused dose-dependent and complete inhibition of the nociceptive spinal reflex (ID50 = 1 mg x kg(-1)). In control animals without paw inflammation, B9858 had no effect. These findings are consistent with other evidence that peptide B1 receptor antagonists inhibit spinal nociceptive reflexes only after induction of B1 receptors by inflammation and support the potential therapeutic utility of B1 receptor antagonists as analgesic and anti-inflammatory drugs.

Feeling below PAR: proteinase-activated receptors and the perception of neuroinflammatory pain

In an article in this issue of PNAS, Jasmin et al. (1) provide new evidence that noradrenaline is a key neurotransmitter in the endogenous pain inhibitory systems in the central nervous system (CNS) of the mouse. They show that this adrenergic inhibitory system interacts with that part of the sensory nociceptive system by using the neuropeptide substance P in a mutually antagonistic manner. They conclude that substance P, when unopposed by tonic release of noradrenaline, is the major factor underlying thermal hyperalgesia. Jasmin et al. also present evidence that the reduced opioid efficacy seen in the absence of noradrenaline is the result of increased NK1 receptor stimulation by endogenous substance P. Their paper (1) is a good example of the way in which critical, and well controlled, experiments on transgenic animals can help to elucidate complex problems in neurobiology. This fascinating study supports other recently published work suggesting that substance P has a key role in pain perception in the mouse by way of critical interactions with other systems, e.g., the PAR2 protease-dependent receptor (2, 3). This fascinating study supports other recently published work suggesting that substance P has a key role in pain perception in the mouse.